Over the last decade, it has become evident that there is a significant correlation between eating a diet rich in fruits and vegetables (foods with high flavonoid content), and a decreased risk for chronic diseases such as cancer. Accordingly, the anti-cancer effects of dietary flavonoids have become an increasing public health interest. Numerous studies in animals and humans have shown that flavonoids are capable of inhibiting carcinogenesis, but the mechanisms by which they act remain largely unknown. Our lab has recently performed a novel biochemical high throughput screen (HTS)in which we identified flavonoids as potent Wnt signal transduction inhibitors. The Wnt pathway is a conserved signaling pathway shown to be important in a number of human cancers. Specifically, abnormal activation of Wnt signaling is present in over 85% of all sporadic cases of colorectal cancer. Given the importance of Wnt signaling in cancer, the possibility that inhibition of the Wnt pathway is one mechanism by which flavonoids exert their anti-cancer effects is especially intriguing. Thus, the main objective of this application is to characterize the role of flavonoids in inhibitingWnt signal transduction through the following specific aims: 1) By performing structure activity relationship studies of the flavonoid compounds identified in our HTS to determine the structural features required for their Wnt inhibitory activities, and 2) By determining the specific target of our flavonoid compounds in the Wnt pathway. The results of these studies will reveal important information on the mechanism by which an important class of dietary compounds, flavonoids, may inhibit cancer, and may lead to the discovery of novel chemotherapeutic compounds. Public health relevance: Flavonoids are a class of chemical compounds found in fruits and vegetables. These compounds have been shown to possess anti-cancer activity, but how they are able to inhibit cancer is unclear. This study aims to elucidate one mechanism by which flavonoids may inhibit cancer;through inhibition of the Wnt pathway, a cell signaling pathway known to be important in the formation of many cancers. Understanding how flavonoids inhibit Wnt signaling will allow us to understand the basis by which these dietary compounds inhibit tumor formation as well as lead to the development of potential chemotherapeutic agents for the treatment of a variety of cancers.